This invention relates to a composition comprising or consisting of components (a) (i) at least one mono-alkanoyl glycerol ester, wherein alkanoyl is selected from C4 to C21 alkanoyl, preferably from octanoyl and decanoyl; and (b) (i) at least one compound selected from cholesterol, phosphatidyl cholines and phosphatidyl glycerols, wherein the acyl moieties of the phosphatidyl moieties are independently selected from C6 to C21 alkanoyl and C6 to C21 alkenoyl.
In this specification, a number of documents including patent applications and manufacturer's manuals is cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.
Peptide-based drugs are typically delivered by injection, since oral delivery by ingestion is often hindered by poor intrinsic permeability and degradation in the gastrointestinal (GI) tract. Nevertheless, the potential therapeutic benefit or oral delivery remains significant, including ease of use and better overall patient compliance.
Mucosal delivery of peptides into the blood stream of a host across various mucosal membranes, such as found in the GI tract, lung, nasal cavity and oral cavity, is possible for a number of peptides and peptide formulations. However, the fraction of an administered dose of unchanged peptide that reaches the systemic circulation (i.e., bioavailability) normally varies depending on the particular route of delivery, peptide and formulation. Thus, the non-invasive delivery of peptide drugs by mucosal routes offers significant flexibility.
For example, delivery of drugs via oral mucosa provides direct access to the systemic circulation through the internal jugular vein, allowing them to bypass the gut and hepatic first-pass metabolism, and enter the bloodstream for rapid on-set of effect. As such, the mucosal lining in the oral cavity represents a promising topical route for the delivery of large therapeutic molecules such as insulin, interferons, and interleukins (Veuillez et al., Eur. J. Pharm. Biopharm. (2001)51:93-109; and Sudhakar et al., J. Control. Release (2006) 114:15-40; and Amin et al., Drug Delivery Technology (2007) 7(3) 48, 50-55).
One drawback of oral mucosal delivery of larger molecules is their poor overall bioavailability. In this regard, various approaches have been explored to improve the oral mucosal absorption of peptides, including use of absorption enhancers to increase mucosal membrane permeability and/or the addition of enzyme inhibitors to increase drug stability. Many substances can function as absorption enhancers, one of the most popular being detergents such as bile acid salts, sodium lauryl sulfate, and the like based on intercellular lipid solubilization (Aungst et al., Intl. J. Pharmaceutics (1989) 53(3); 227-35; Druker, D. J., Curr Pharm Design (2001) 7(14):1399-1412; and Berstein, G., Drug Development Res. (2008) 67(7):597-599). Cyclic compounds such as crowns have also been used (WO 08/037,484).
Reservoir-type devices filled with drug, along with cholate as a penetration enhancer, have been reported for buccal delivery of insulin (U.S. Pat. Nos. 4,671,953; 4,863,737; 5122127; and 5,132,114). Lipid vesicles composed of soybean phosphatidylcholine, cholesterol, and sodium deoxycholate, has been reported to enhance insulin bioavailability as well (Yang et al., Chem. Pharm. Bull. (2002) 50:749-753). Gels composed of Pluronic F-127 (PF-127) containing insulin and unsaturated fatty acids, such as oleic acid (18:1), eicosapentaenoic acid (20:5), or docosahexaenoic acid (22:6) have been reported (Morishita et al., Int. J. Pharm. (2001) 212:289-293). The absorption enhancer lysalbinic acid, which is a product of the alkaline hydrolysis of egg albumin and a mild detergent, also has been reported for molecules such as α-interferon and insulin (Starokadomskyy et al., Int. J. Pharm. (2006) 308:149-154). Various delivery systems have been reported for buccal delivery of glucagon-like insulinotropic peptide (GLP-1) (U.S. Pat. Nos. 5,863,555 and 5,766,620).
A variety of mucoadhesive dosage forms also have been reported to increase resident time of the delivery system in the oral cavity (Ishida et al., Chem. Pharm. Bull. (1981) 29:810-816; and Senel et al., Curr. Pharm. Biotechnol. (2001) 2:175-186), including, for example, pelleted mucoadhesive polymeric nanoparticles (Venugopalan et al., Pharmazie (2001) 56:217-219), and mucoadhesive tablets (Hosny et al., Boll. Chim. Farm. (2002) 141:210-217).
Mucosal dosage forms employing various solvents have also been reported, such as insulin with soybean lecithin and propanediol (Xu et al., Pharmacol. Res. (2002) 46:459-467), and buccal aerosol sprays and capsules using non-polar solvent (U.S. Pat. No. 5,955,098). Pulmonary delivery formulations of a solution or suspension of various organic solvents have been reported, for example, where the solvent is a class 3 residual solvent such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol (U.S. Pat. No. 6,680,715).
Despite advances, mucosal delivery systems often include absorption enhancing formulations that exhibit side effects, such as causing irritation of the various mucosal linings in the mouth or airways. Another problem is the repugnant taste of many compositions, particularly for bile salts, pointing to likely issues with patient acceptance and compliance. A different issue relates to the volume required for delivering a sufficient amount of an active peptide ingredient for biological effect, storage stability, and reproducibility.
Various peptides, uses, formulations and delivery routes and systems are reported in the following; U.S. Pat. Nos. 4,671,953; 4,863,737; 5,122,127; 5,132,114; 5,348,701; 5,424,286; 5,545,618; 5,614,492; 5,631,224; 5,766,620; 5,869,082; 6,268,343; 6,312,665; 6,375,975; 6,436,367; 6,451,286; 6,458,924; 6,660,715; 6,676,931; 6,770,625; 6,867,183; 6,902,744; 6,969,508; 6,977,070; 6,998,110; 7,030,082; 7,070,799; 7,169,410; 7,196,059; and International Patent Application Nos.: WO 9715297; WO/1999/016417; WO/2002/064115; WO/2003/024425; WO/2004/105790; WO/2006/025882; WO/2006/037811; WO/2006/103657; WO/2006/105615; WO/2006/127361; WO/2006/135930; WO/2007/014391; WO/2007/065156; WO/2007/067964; WO/2007/083146; WO/2007/121256; WO/2007/146448; WO/2008/037484; WO/2008/145728; WO/2008/145732; and WO/2008/016729.
Various references discuss alternatives to subcutaneous injection (s.c.) of peptides and uses, including peroral, intra oral (buccal/sublingual), rectal, transdermal, intra nasal, and intra pulmonary delivery routes: Touitou, E., J. Controlled Rel (1992) 27:139-144; Amin et al., Drug Delivery Technology (2007) 7(3) 48, 50-55; Aungst et al., Pharmaceutical Research (1988) 5(5):305-308; Aungst et al., Intl. J. Pharmaceutics (1989) 53(3):22735; Berstein, G., Drug Development Res. (2006) 67(7):597-599; Druker, D. J., Curr Pharm Design (2001) 7(14):1399-1412; Hosny et al., Bollettino Chimico Farmaceutico (2002), 747(3):210-217; Khafagy et al., Advanced Drug Delivery Reviews (2007) 59(15): 1521-1546; Lassmann-Vague et al., Diabetes & Metabolism (2006) 32(5, Pt 2):513-522; Morishita et al., Intl. J. Pharmaceutics (2001) 212(2):289-293; Patel et al. Drug Delivery Technology (2006) 6(3)48-60; Pillion et al., J. Pharm. Sci. (1995) 84(11):1276-1279; Portero et al., Carbohydrate Polymers (2007) 68(4):617-625; Pozzilli et al., Metabolism, Clinical and Experimental (2005) 54(7):930-934; Owens, D. R., Nature Reviews Drug Discovery (2002) 1(7):529-540; Rossi et al., American J. Drug Delivery (2005) 3(4):215225; Sadrzadeh et al., J. Pharm Sci (2007) 96(8): 1925-1954; Starokadomskyy et al., Intl. J. Pharmaceutics (2008) 308(1-2):149-154; Xu et al., Pharmacological Research (2002) 46(5:459-487; Yang et al., S.T.P. Pharm. Sciences (2001) 11(6):415-419; Yang et al., Chemical & Pharmaceutical Bulletin (2002) 50(6):749-753; Klibanov et al. (1995 supra) reported on lyophilization of various biomolecules from aqueous solutions of different pH's and their subsequent solubility in methanol and ethanol.
US 2006/0178304 discloses lyophilization of various glucagon-like peptides from aqueous solutions or suspensions of different phi's and their subsequent solubility in aqueous solutions or suspensions.